DESCRIPTION: (provided by the applicant): Malaria is a major infectious disease. Conservative estimates predict 2-300 million people are afflicted and over a million children die from the infection each year. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of the parasite not found in host cells provides one approach to new drug and vaccine development. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P. falciparum is its development in a vacuole when it infects the red cell. This host cell is non-endocytic and does not invaginate its plasma membrane. Yet P. falciparum induces both membrane invagination and vacuole formation in these cells. Thus it must exploit non-endocytic mechanisms to take up solutes and macromolecules. The long-term aim of this proposal is to identify and characterize the mechanisms by which malaria parasites develop their vacuoles for their implications on drug and toxin delivery. The studies will contribute to our understanding of the basic biology of the parasite as well as delineate mechanisms of drug resistance and vaccine delivery, and thereby contribute to human health. Molecular, genetic tools using transfection, genomics combined with high resolution imaging techniques and biochemical subcellular fractionation assays will be used to identify and purify host membrane components that are recruited into the vacuole and evaulate their associated signals required for interactions with specific lipids and protein components of both host and parasite origin that underlie vacuole formation in the infected red cell. The consequence of ablation of host or parasite gene products or expression of transdominant forms of mutant parasite genes on vacuole formation; drug and toxin uptake and parasite growth will be evaluated in in vitro cultures. These studies maybe important for understanding mechanisms of chemo and immunprophylaxis directed against a major human pathogen.